Enzyme could help explain life's origin

John Gastaldo

Gerald F. Joyce, right, studies the origins of life at The Scripps Research Institute. A team headed by Joyce and post doctorate fellow Jon Sczepanski evolved an enzyme that could help explain the RNA world hypothesis.

Gerald F. Joyce, right, studies the origins of life at The Scripps Research Institute. A team headed by Joyce and post doctorate fellow Jon Sczepanski evolved an enzyme that could help explain the RNA world hypothesis. (John Gastaldo)

Enzymes are catalysts that speed up chemical reactions. This particular enzyme, called a ribozyme, speeds up the production of the genetic molecule RNA by one million times. Moreover, it can make two different kinds of RNA, left-handed and right-handed. This has never been demonstrated before.

The study, published Wednesday in Nature, could solve a problem in a widely accepted part of origin-of-life theory called the RNA world hypothesis. It holds that RNA preceded DNA as the carrier of heredity. But presumably, left-handed and right-handed RNA existed on the primitive earth, while in nature today only right-handed RNA exists.

Explaining how the left-handed RNA could have vanished would represent a major step toward linking life today to molecules billions of years ago, said study leader Gerald Joyce and first author Jonathan Sczepanski.

The ribozyme provides a clue: Like M.C. Escher's famous illustration of two hands drawing each other, the right-handed version produces left-handed RNA, and the left-handed ribozyme makes right-handed RNA. A ribozyme like this is sufficient to get molecular replication under way.

Later on, the scientists say the right-handed version experienced a mutation that greatly increased its fitness. At that point, it could discard the two-sided copying mechanism.

This event, if it happened, occurred so long ago that no trace of it is left in modern life. Today’s life doesn’t even recognize left-handed RNA if introduced by a scientist. The molecule can exist and even replicate in biological structures without provoking an immune response or any sign of its presence.

Joyce calls this “ghost biology.”

The implications from the study go beyond helping explain how life might have originated.

If life can emerge in both the way we know and its mirror-image version, astrobiologists could refine their estimates of the probability of life arising on other worlds.

Closer to home, doctors could get a new way of intervening in diseases that doesn’t provoke immune reactions the way conventional drugs can do.

The study also removes a major roadblock in the RNA world theory, one proposed by Joyce himself 30 years ago. Random construction of RNA from left and right nucleotides present on the early earth would inevitably bring together both types in one molecule. When that happens, it “poisons” the RNA building process and it stops.

But if the enzymes exclusively constructed a left- or right-sided molecule, there would be no poisoning. Evolution would be free to take off.

Selection and evolution

The study began with a "soup" of about one quadrillion right-handed short RNA molecules, in random sequences. These molecules were tested to see if they could catalyze building left-handed RNA molecules. Those that could were selected and used to generate more catalysts.

After 10 of these rounds, a prototype ribozyme emerged. The researchers modified the ribozyme and put it through six more expansion-and-selection rounds. After trimming off nucleotides that weren't needed, the result was a ribozyme that speeded up RNA synthesis by a millionfold.

The study has its limitations. The ribozyme replicates certain RNA sequences better than others, meaning it is not a general-purpose copying mechanism. Joyce and colleagues are attempting to evolve a better-functioning version.

“Overall, it is a beautiful piece of work from a leader in the field, and the problem it addresses has not been approached by anyone else as far as I’m aware,” said Charlie Carter, a structural biologist at the University of North Carolina’s Chapel Hill branch.

However, Carter said the study leaves more unanswered questions. “How do you get from the pre-biotic soup to this ribozyme?” he said.

Peter Unrau, a molecular biologist who studies the properties of RNA at Simon Fraser University in Burnaby, British Columbia, said, “This paper positions itself at the transition from non-living to living systems.”

Unrau said it is easy to imagine that one-half of the two-handed RNA mixture could gain an advantage and compete the other half into oblivion.

As the system expanded, taking in molecules of one side or another, it would eventually exhaust the supply of these “handed” molecules. At that point, it would need to find a way to live off of molecules that didn’t exhibit handedness. The first side that did that would win.

Ghost RNA

One of the strangest properties of the evolved ribozyme is its “ghost” property of acting in biological materials without provoking any response, Joyce said.

“If you mix right-handed RNA with biological fluids, it’s degraded instantly,” Joyce said. “So it’s hard to use RNA as a tool. If you make the mirror image of RNA, there’s nothing in biology that can degrade it.”

Recently, Joyce and colleagues built a left-hand ribozyme that synthesizes left-hand RNA, as opposed to the mirror-image enzyme described in this paper.

“The left-handed self-replicating RNA can replicate in human serum, because there’s nothing in human serum that can touch it,” Joyce said. “It passes as a ghost through our biology.”

However, this left-handed RNA can’t grow from right-handed RNA nucleotides, Joyce said. These nucleotides must be supplied from the laboratory. That provides a check on any untoward consequences.

Biotech companies have taken a growing interest in RNA drugs over the last decade because a vast number of RNA sequences have been identified as regulators, increasing or reducing the production of proteins or causing other effects.

Using left-handed RNA to interfere with the activity of right-handed RNA in theory could in theory work better, because the “ghost” RNAs would invisibly reach their target. But that concept needs a lot more research before it can be tested in therapeutics, Joyce said.